Week 8 Flashcards by Lucy Cooper

Functions of the skeleton

Mechanical- support and muscle attachment
Protective- for vital organs and marrow
Metabolic- ion homeostasis especially calcium and phosphate

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Basic structure of bones

Epiphysis- end part of long bone, initially growing separately form shaft
Diaphysis- shaft or central part of long bone
Metaphysis- wide portion of long bone and regions of bone where growth occurs
Cortical bone- dense and solid and surrounds marrow space (compact, lamellar)
Cancellous (trabecular) bone- bone involved in bone turnover
Articular cartilage
Growth (epiphysial) plate

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What is bone made of

Specialised connective tissue
Extracellular matrix which is able to calcify
Collagen fibres
Non collagenous proteins essential to bone function (osteocalcin, osteonectin, osteopontin)
Mineralisation (calcification) occurs with formation of hydroxyapatite crystals (complex of calcium and phosphate crystals). Embedded in bone to give bone structural integrity
Contains several types of cells

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Cell types within bone

Osteocytes
Osteoblasts
Osteoclasts

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Osteocytes

Deep embedded in calcified bone matrix, have long processes which contact other osteocytes and osteoblasts. Important for regulation of bone turnover

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Osteoblasts

Bone forming cells which produce matrix constituents and aid calcification. Collagen and hydroxyapatite
Originate from mesenchymal stem cells (bone marrow stem cells or connective tissue mesenchymal cells)
Classical marker- alkaline phosphatase (regulator of bone mineralisation), osteocalcin (non-collagenous protein)

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Osteoclasts

Bone resorbing cells usually found in contact with calcified bone surface- in lacunae
Multinucleated- originate from bone marrow lineage
Produce acid (to resorb mineral) and enzymes (to resorb matrix)
Attachment to bone very important- integrins
Classical markers- carbonic anhydrase, tartrate-resistant acid phosphatase (TRAP), RANK, calcitonin receptor

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What is an osteoid

Unmineralised bone tissue

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Osteoclasts development

Osteoblast contain RANK ligand (RANKL) and attaches to RANK receptor on osteoclast precursor. Regulated by VIT D, PTH
Then forms a mature osteoclast
Osteoprotegerin OPG, interacts with RANK ligand and prevent osteoclast interaction. Regulated by estrogens
Denosumab- limits production of mature osteoclast by acting as a decoy for RANK ligand receptor process

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Bone cells and bone remodelling

Dynamic process
Osteoclast binds to bone surface (integrens)
Resorption
Osteoclast releases acid and enzymes forming resorption pit. Releasing Ca2+/PO4 +collagen
Forms osteoid
Layers of collagen mineralised to form new bone by osteoblasts

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The bone remodelling cycle (trabecular bone)

Resting surface
Osteoclast, bone resorption
Osteoblast, reversal phase
Bone formation (osteoid)
Bone formation (osteoid- mineralisation front)
Resting surface
Hope that same amount bone produced as bone resorbed

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Osteoporosis

Loss of bone mass (increased risk of fracture)
Increase in bone mass as age increases, reach peak bone mass at 20-30
Osteoblasts dominating osteoclasts, more bone mass
As you get older process reverses osteoclast dominate, bone resorption dominates over formation, bone mass decreases

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Bone and calcium homeostasis

Bone - protect vital organs, support muscles, reservoir of calcium. >99% calcium
Soluble calcium- excitable tissue, muscle contraction, nerves, cell adhesion <1%

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Calcium homeostasis

GI tract, absorb Ca
Kidney, homeostatically controlling ca release
Bone

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Parathyroid hormone PTH

84 amino acid peptide but biological activity in first 34 amino acids (PTH 1-34), half life 8 mins
Normal adult reference range =1.6-6.9 pmol/L
Binds to cell membrane G protein coupled receptors
Causes signalling inside cell. Mainly in kidney and osteoblasts

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Hypocalcaemia

Calcium sensitive receptors in parathyroid
Increased PTH secretion
Increase bone resorption,
Kidney: increase urinary phosphate, decrease urinary calcium, increase 1,25D3 production (active from vitD)
Intestine: increase calcium and phosphate absorption
Increase serum calcium
Negative feedback mechanism

Vitamin D

Best used to refer to precursor form 25-hydroxyvitamin D3 (25D3)
Numbers after name reflect origin, Vit D2 of plant origin, Vit D3 of animal origin
Numbers before name reflect changes (hydroxylations) in Vit D that change its biological activity (1,25D3) binds to intracellular vitamin D receptor VDR, active from of vit D made in kidneys
25D3 is easier and cheaper to measure so used most in hospitals
<50nmol/L [20ng/ml] is insufficient

Where do we get vit D from

UV radiation mainly - skin (7-dehydrocholesterol)- Vit d3
Diet—vitamin D3
Into blood , into liver (25D3), into kidney which activates 25D3, stimulated by PTH to produce 1,25D3

Calcitonin

Produced by thyroid c-cells (parafollicular- which dont produce thyroid hormones)
Calcitonin released in hypercalcaemia, inhibits bone resorption (by direct effect on osteoclasts), no ca released
Not essential to life

Hypercalcaemia

Thyroid increases calcitonin production, decreases bone resorption
Kidney: decrease urinary phos, increase urinary calcium, decreased 1,25D3 production
Intestine: decrease calcium and phosphate absorption
Decrease serum calcium

Fibroblast growth factor 23 (FGF23)

Phosphate regulating hormone
Produced by bone cells (osteocytes and maybe osteoblasts)
Released in response to high serum PO4
Increase renal excretion of PO4 and suppresses renal synthesis of active vit D
Main inducer of FGF23 appears to be 1,25D3

Hyperphosphataemia

Osteocytes sense change and produce more FGF23
Increase FGF23 in bone, suppresses 1,25D3
Kidney: increase in urinary phos, decrease urinary calcium
Dominant effects on kidney reverses high phosphate
Decreasing serum phosphate

Primary hyperparathyroidism

Raised serum PTH:
Parathyroid tumour (usually benign adenoma)
Causes hypercalcaemia and low serum phosphate
Loss of negative feedback. Treatment is surgery, can be given calcimimetics
Clinical features: lethargy/confusion, thirst/polyuria, renal stones, constipation, pancreatitis, joint pain, fracture, depression, hypertension

Calcimimetics

Drugs that are allosteric activators of calcium sensing receptor. So enhancing signalling and decreasing PTH release

Rickets/ osteomalacia

Deficiency of VIT D Lack of mineralisation of collagen component of bone (osteoid) , failure to absorb sufficient calcium from GI tract Called rickets when affecting growing skeleton, osteomalacia when affects adult Dietary/lack of sunlight, rarely inherited (mutations in VIT D receptor, 1-alphahydroxylase defects (enzyme that produces active vit d), x-linked hypophosphataemic rickets) Treatment vit D replacement

Rickets symptoms

Osteoid at growth plate is weak (bow legs). Growth plate is where bones developed , area of tissue near ends of long bones in children and teens, determine future length and shape of mature bone Growth plate expands to compensate (swollen joints)

Osteomalacia symptoms

Bone pain, pseudofractures

Rickets and osteomalacia leads to hypocalcaemia

Since not enough vit D, so not enough 25D3, therefore there’s not enough substrate for the enzyme in the kidney so not enough 1,25D3 formed Body cant absorb enough minerals Decreasing serum calcium more

Secondary hyperparathyroidism

Secondary to renal disease Increased serum phosphate, decreased activation of vit D to 1,25D3, kidneys not working Treatment with phosphate binders or vit D analogues (synthetic forms of active form of VIT D) FGF23 trying to prevent hyperphosphataemia Lower serum calcium Decreased absorption of ca and phos Ca and 1,25D3 low leads to osteomalacia Phosphate and calcium disorder

Oncogenous osteomalacia

High serum FGF23 and low serum 1,25D3 due to benign tumour secreting FGF23 Ricket like phenotype

X-linked hypophosphaemic rickets

PHEX protein targets FGF23. Mutations in the PHEX gene lead to elevated FGF23 and suppressed 1,25D

Osteoporosis

Loss of bone mass/density= both mineral and non mineral bone decreased Leads to increased fracture risk, wrist, spine, hip Osteoporosis of aging Postmenopausal osteoporosis= rapid decline in female bone density following decline in oestrogen Steroid-induced osteoporosis= decline in bone density associated with use of steroids as therapy for inflammatory disease

Spinal osteoporosis

Compression fractures from vertebrae collapsing on themselves Kyphotic spine Kyphosis is curvature of spine causing top to be more rounded

Osteoporosis therapeutic options

Hormone replacement therapy- oestrogen, as oestrogen deficiency increases bone remodelling and bone resorption Inhibition of osteoclast development- denosumab (RANK ligand antibody), blocks ligand on osteoblasts from interacting with osteoclasts, decreased differentiation of pre-osteoclasts Inhibition of osteoclast activity- bisphosphonates, disrupt intracellular enzymes required for osteoclast activity Stimulation of osteoblast activity (anabolic)- use of PTH stimulates osteoblasts>osteoclast. Teriparatide. Stimulates bone formation

Osteoporosis prevention options

Diagnosis of osteoporosis risk is made based on assessment of low bone mineral density BMD using DEXA or ultrasound and lab investigations. Optimal BMD may prevent osteoporotic fracture Exercise may enhance osteocyte activity through bone stress Vit D and calcium could help maintain general bone health Avoid smoking and high levels of alcohol intake

What is tetany

Symptom that involves involuntary muscle contractions and overly stimulated peripheral nerves Often caused by electrolyte imbalance most often low calcium levels

Symptom if you remove parathyroid glands

Tetany